Normal sexual function involves a complex interaction of emotional, neuronal, vascular and hormonal factors. In addition sexuality incorporates personal, family, social and religious beliefs and is altered with aging, health status, and personal experience (Tomlinson, 2004).
A disruption in any of these areas may lead to sexual dysfunction. Sexuality in females may particularly involve many brain-mediated responses. About 43 percent (40 million) women in the US experience some form of sexual dysfunction. Sexual dysfunction in a female may include hypoactive sexual desire disorders, arousal disorders, orgasmic, or sexual pain disorders. Physical and emotional stimulation lead to breast and genital vasodilation and clitoral engorgement. In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce an orgasmic response.
Male sexual dysfunction may include erectile dysfunction and impotence. Erectile dysfunction (ED) in the male is defined as the inability to maintain an erect penis with sufficient rigidity to allow sexual intercourse. Erectile dysfunction is a common problem affecting about 30 million men in the US (NIH, 1993). It is estimated that the world-wide incidence of ED will increase from 152 million in 1995 to 322 million men by the year 2025 (Ayta et al; 1999).
It is an age-related condition with about 39% of men over 40 and 67% of men over 70 years suffering from erectile dysfunction (Seftel, 2003). Many conditions such as atherosclerosis can reduce blood flow to the penis, causing ED. Other conditions such as diabetes, hypertension, hyperlipidemia, and cigarette smoking also will lead to ED. Normal erection is mediated through the central nervous system which transmits psychogenic and sensory stimuli to the sympathetic nervous system which controls penile blood flow (Steif, 2003). The arterial blood vessels dilate and deliver blood to the penis, which enables the corpora cavernosa sinus system to become engorged with blood. Vasodilation of the cavernosal arteries and closure of the venous drainage in the penis produce an erection. The hypothalimic-pituitary-testicular axis also has a role as testosterone is required for normal libido (Rhoden, 2002).
Any psychological, neurologic, vascular, urogenital and endocrine abnormality may cause erectile dysfunction. Diabetes is one of the most common causes of ED (DeAngelis, 2001; Utkan, 2001). Other factors leading to ED are smoking, vascular disease, atherosclerosis, hypertension (Burchardt, 2000), hypercholesterolemia, renal failure, injury, surgery, hypogonadism and drugs. A variety of drugs can initiate and accelerate erectile dysfunction (Galle, 2003). These drugs include antihypertensives like beta adrenoreceptor blockers, diuretics, digoxin, antidepressants and antipsychotics, histamine-2 receptor antagonists, alcohol, opiates, amphetamines, and cocaine.
About 80% of patients with ED develop the condition because of a drug or some organic illness. The remaining 20% have a primary psychogenic cause (Rosen, 2001). Psychogenic ED may be treated with behavioral therapy (DeBeradis, 2003), which is successful in half of the patients. If ED is due to organic illness, or if it is psychogenic, but cannot be corrected by behavioral therapy, drug therapy is used (Galle, 2003; Carson 2000).
Current Methods for Treatment of ED
    1. Vacuum constriction devices suitable for patients with venous disorders (Dutta 1999).    2. Prosthetic devices which are directly implanted into paired corporal bodies. These devices may be rigid, malleable, hinged, or inflatable.    3. Vascular reconstructive surgery is used for patients with disorders of the arterial system.    4. Testosterone (injection or skin patches) can be used for men with documented androgen deficiency. Men with prostatic cancer or elevated PSA should not be given testosterone.    5. Direct injection of prostaglandin E1 (alprostadil) into the penis. Common side effects are dizziness, local pain, fibrosis, and infection (Chiang, 2000).    6. Drugs like apomorphine, dopamine receptor agonists, phentolamine, yohimbine, papaverine, vasoactive intestinal peptide, melanocortin receptor agonists, and combinations of these drugs (Carson 2000; Goldstein 2000).    7. Phosphodiesterase (especially type 5) inhibitors (McMahon, 2000).Phosphodiesterase Inhibitors
Phosphodiesterase (PDE) inhibitors are a class of intracelleular enzymes which mediate the catabolism of second messengers like cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These enzymes have been classified into at least eleven groups (types I-XI) and various subclasses based on their amino acid sequence and substrate specificity (Polson, 1996; Trophy, 2000). The various PDE differ in their tissue, cellular distribution, and their specificity towards cAMP or cGMP. (table 1). So phosphodiesterase inhibitors have applications in a number of disorders including vascular, neuronal and inflammatory disorders (Zang 2002, Martin 2002, Grootendorst 2002, Burnouf, 2002). PDE inhibitors are drug candidates for the treatment of a number of disorders including heart failure, depression, asthma, inflammation, sexual dysfunction, and erectile dysfunction. Phoshodiesterase 4D has been shown to have a role in ischemic stroke (Gretarsdottir, 2003).
TABLE 1Human Phosphodiesterases (PDE)PDESpecificitytypeTissue localizationDisorderInhibitorscAMP3Heart, corpusEnoximone,cavernosum,piroximoneplatelets, smootholprinone,muscle (vascular,motapizone,visceral, bronchial),milrinone,vagus nerve, liver,amrinone,kidney endothelium,cilostamide,lymphocyte, mastcilostazolcell4Kidney, lung, heart,InflammatoryRolipram,skeletal muscle,disorderspiclamilastsmooth muscledepressiontibenelast,(vascular, visceral,allergy, asthmabenafentrineairway),strokezardaverine,endothelium,tolafentrineinflammatory cells,platelets, vagusnerve7Skeletal muscle,Dipyridamoleheart, kidney,airways,lymphocytes,monocyte eosinophil8Testis, ovary, ileum,Dipyridamolecolon, heart, brain,kidney, pancreas,airways, monocyte,thyroidcGMP5Corpora cavernosa,ErectileSildenafil,platelets, skeletaldysfunctionTadalafilmuscle, smoothfemale sexualVardenafilmuscle (vascular,dysfunction,zaprinast,visceral, airway),pulmonarydipyridamolekidney, vagus nervehypertesionpapavenneImpotence6Retina (rods andPDE 5cones)inhibitors9Spleen, smallZaprinastintestine, braincAMP &Heartt, brain,MIMX,cGMPkidney, liver,vinpocetineskeletal muscle,phenothiazinessmooth muscle(vascular, visceral,airway), vagusnerve2Adrenal cortex,EHNA (erytro-brain, heart, liver,9-[2-hydroxyl]corpus cavernosum,adenine)platelet, airwaysmooth muscle10Brain (putamen,IBMXcaudate nucleus)11Skeletal muscle,zaprinastprostate, kidney,dipyridamoleliver, pituitary,salivary glands,testisNitric Oxide and Erectile Dysfunction
Nitric oxide (NO) formed from L-arginine by the enzyme nitric oxide synthase (NOS) is the prime mediator of endothelium-dependent smooth muscle relaxation and penile erection (Burnett, 1992). NO regulates vascular tone and promotes blood vessel relaxation and also has other roles in immune system, nervous system, and inflammation. NO is synthesized and released by neuronal (nNOS) and endothelial (eNOS). Both eNOS and nNOS are constitutively expressed in the endothelium and penile nerve endings (Hedlund, 2000; Bloch, 1998). Upon sexual stimulation NO is released from nerve endings, or from endothelial cells stimulated by acetylcholine from cholinergic nerve endings (Lue, 2000). It is likely that penile erection is mediated by both nNOS and eNOS. Reduced androgen levels, found in elderly men cause impaired expression of penile NO synthesis. NO synthesis is also impaired by hypertension, high levels of oxidized LDL, TNF alpha, and cAMP. NO activates a soluble guanyl cyclase that forms cyclic guanosine mononphosphate (cGMP). Cyclic GMP is the primary second messenger that mediates penile erection. Phosphodiesterase 5 inhibitors like sildenafil prevents the degradation of cGMP and enhances erectile function. NO activates prostaglandin synthesis. The prostacyclin thus formed along with NO released by eNOS and nNOS stimulation causes relaxation of smooth muscle cells. Impaired NOS function, rather than NOS expression is considered to be the cause of insufficient NO production and the inability to stimulate the penile corpora cavernosa to elicit a normal erectile response Gonzalez-Cadavid, 2000; Maas, 2003). Prostaglandin E1 and its derivative alprostadil, which induce relaxation mainly through cAMP also enhance erection (Porst, 1996).
Inflammatory processes cause a shift from vasodilatory to vasoconstrictor eicosanoids. Under such conditions NO generated from eNOS and nNOS is not sufficient to cause smooth muscle relaxation.
Oxidative stress contributes to the development of atherosclerosis, endothelial dysfunction, and ED. By reacting with NO itself, or by interfering with NO-mediated pathways, reactive oxygen species (ROS) could contribute to erectile dysfunction. Thus antioxidants will enhance erectile function by scavenging ROS and enhancing bioavailability of NO.
Examples of type V (5) phosphodiesterase inhibitors include, but not limited to, sildenafil, tadalafil, vardenafil, avanafil, Zaprinast®, papaverine and dipyridamole. Other type 5 PDE inhibitors are disclosed in PCT Publication Nos. WO 94/28902, WO 96/16644, U.S. Pat. No. 6,338,862 and U.S. Pat. No. 6,476,037.
Other Potential Applications of PDE5 Inhibitors
                1. Enhance sexual function in men following prostate surgery.        2. Enhance sexual function in hypogonadal men by combining testosterone and PDE inhibitor.        3. Treatment of premature or rapid ejaculation.        4. Enhance sexual function in women        5. Enhance endothelial function in patients with primary pulmonary hypertension.        6. Treatment of urinary tract symptoms due to benign prostatic hyperplasia.        7. Treatment of urinary incontinence.        8. Treatment of sickle cell anemia by combination therapy with hydroxyurea        9. Enhance sexual function in men and women by combination therapy with antioxidants, vitamin E, arginine, apomorphine , dopamine agonists, alpha adrenergic blocker etc.        10. Prevention and treatment of stroke.        11. Treatment of coronary and cerebral vascular diseases.        12. Treatment of thrombosis        13. Treatment of ocular hypertension        14. Treatment of pregnancy-induced hypertension.        15. Treatment of anal sphincter disorders (Jones, 2002).        16. Treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyloid diseases, Prion diseases.        17. Treatment of other diseases where cGMP is implicated to have beneficial effects.        
Side Effects and Complications of PDE5 Inhibitors
The side effects of PDE inhibitors include hypotension, flushing, headache, nasal congestion and heartburn and these effects are dose dependent (Moreira, 2000). The incidence of cardiovascular events and deaths have been reported with the use of PDE 5 inhibitors (Lim, 2002). This may be due to the fact that PDE5 inhibitors dilate the coronary arteries which makes the patient feel better. This may lead to vigorous physical activity (exercise or intercourse). Such activity may lead to ischemia and heart attack. Also interaction with other drugs including nitroglycerine poses substantial risks. The visual side effects of PDE 5 inhibitors are due to the inhibition of PDE 6 found in the retina. Currently available therapies for ED are palliative, have significant failure rates and side effects, and require treatment prior to each sexual encounter. So novel methods of treatment for patients unresponsive to current treatments are required. In ED, the activity of penile NOS is reduced, or the NO synthesis is not sufficient to produce a normal erectile response. Therefore, stimulation of penile NO synthesis seems to be the ideal treatment for ED. Use of synthetic NO donor compounds have not proved successful due to poor stability and delivery problems of these compounds. Enhancing NO synthesis by administration of the substrate L-arginine is another approach. But the availability of L-arginine is not a rate-limiting step for NOS. Administration of massive doses of L-arginine for long-term is necessary to produce any detectable increase in NO production. This invention describes a practical and efficient method for stimulation of nitric oxide production and enhancing the efficacy of PDE 5 inhibitors in the treatment of ED and other disorders.
Brain mechanisms, particularly activation of dopamine receptors play a major role in normal sexual function (Giuliano, 2001). PDE 5 inhibitors have no effect on brain dopamine activity. Apomorphine and other agents that enhance dopamine also enhance erectile function (Stief, 2003). But these dopaminergic drugs do not enhance penile blood flow. Deprenyl and other MAO inhibitors elevate dopamine levels in the brain and thus can augment sexual function (Knoll, 1989).
Deprenyl and other propargylamine compounds will enhance the efficacy of PDE 5 inhibitors by several mechanisms including stimulation of nitric oxide production and enhanced dopamine activity.